Lipoxygenase enzymes catalyze the conversion of arachidonic acid into a number of biologically active products, including the leukotrienes and 5-hydroeicosatetraenoic acid (5-HETE). A variety of biological effects are associated with these products of lipoxygenase metabolism of arachidonic acid, and several have been implicated as important mediators in various pathophysiological states. For example, the leukotrienes LTC.sub.4 and LTD.sub.4 are potent constrictors of human airways in vitro, and aerosol administration of these substances to non-asthmatic volunteers induces broncho-constriction.
On the other hand, 5-HETE and the leukotriene LTB.sub.4 are potent chemotactic factors for inflammatory cells such as polymorphonuclear leukocytes, and have been found in the synovial fluid of rheumatoid arthritic patients. Leukotrienes have also been implicated as important mediators in asthma, atherosclerosis, rheumatoid arthritis, gout, psoriasis, acne, allergic rhinitis, adult respiratory distress syndrome, Crohn's disease, endotoxin shock, inflammatory bowel disease, ischemia-induced mYocardial injury and central nervous system pathophysiology, among others. The biological activity of the leukotrienes has been reviewed by Lewis and Austen, J. Clinical Invest. 73:889 (1984), and by J. Sirois, Adv. Lipid Res. 21:78 (1985).
Lipoxygenase enzymes are thus believed to play an important role in the mediation of asthma, allergy, arthritis, psoriasis, inflammation and other pathologies. Because inhibition of the lipoxygenase enzymes blocks the biosynthesis of these mediators, lipoxygenase inhibitors are expected to provide an effective means for the systemic and/or symptomatic treatment of these diseases.